Lysophosphatidic acid and sphingosine-1-phosphate promote morphogenesis and block invasion of prostate cancer cells in three-dimensional organotypic models

Ville Härmä, Matias Knuuttila, Johannes Virtanen, Tuomas Mirtti, Pekka Kohonen, Panu Esko Kovanen, A Happonen, S Kaewphan, I Ahonen, Olli Kallioniemi, Matthias Nees, R Grafström, J Lötjönen

Tutkimustuotos: ArtikkelijulkaisuArtikkeliTieteellinenvertaisarvioitu

Kuvaus

Normal prostate and some malignant prostate cancer (PrCa) cell lines undergo acinar differentiation and form spheroids in three-dimensional (3-D) organotypic culture. Acini formed by PC-3 and PC-3M, less pronounced also in other PrCa cell lines, spontaneously undergo an invasive switch, leading to the disintegration of epithelial structures and the basal lamina, and formation of invadopodia. This demonstrates the highly dynamic nature of epithelial plasticity, balancing epithelial-to-mesenchymal transition against metastable acinar differentiation. This study assessed the role of lipid metabolites on epithelial maturation. PC-3 cells completely failed to form acinar structures in delipidated serum. Adding back lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) rescued acinar morphogenesis and repressed invasion effectively. Blocking LPA receptor 1 (LPAR1) functions by siRNA (small interference RNA) or the specific LPAR1 inhibitor Ki16425 promoted invasion, while silencing of other G-protein-coupled receptors responsive to LPA or S1P mainly caused growth arrest or had no effects. The G-proteins Gα12/13 and Gαi were identified as key mediators of LPA signalling via stimulation of RhoA and Rho kinases ROCK1 and 2, activating Rac1, while inhibition of adenylate cyclase and accumulation of cAMP may be secondary. Interfering with these pathways specifically impeded epithelial polarization in transformed cells. In contrast, blocking the same pathways in non-transformed, normal cells promoted differentiation. We conclude that LPA and LPAR1 effectively promote epithelial maturation and block invasion of PrCa cells in 3-D culture. The analysis of clinical transcriptome data confirmed reduced expression of LPAR1 in a subset of PrCa's. Our study demonstrates a metastasis-suppressor function for LPAR1 and Gα12/13 signalling, regulating cell motility and invasion versus epithelial maturation.
Alkuperäiskielienglanti
LehtiOncogene
Vuosikerta31
Numero16
Sivut2075-2089
Sivumäärä16
ISSN0950-9232
DOI - pysyväislinkit
TilaJulkaistu - 2012
OKM-julkaisutyyppiA1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä, vertaisarvioitu

Tieteenalat

  • 1182 Biokemia, solu- ja molekyylibiologia
  • 3122 Syöpätaudit

Lainaa tätä

Härmä, Ville ; Knuuttila, Matias ; Virtanen, Johannes ; Mirtti, Tuomas ; Kohonen, Pekka ; Kovanen, Panu Esko ; Happonen, A ; Kaewphan, S ; Ahonen, I ; Kallioniemi, Olli ; Nees, Matthias ; Grafström, R ; Lötjönen, J. / Lysophosphatidic acid and sphingosine-1-phosphate promote morphogenesis and block invasion of prostate cancer cells in three-dimensional organotypic models. Julkaisussa: Oncogene. 2012 ; Vuosikerta 31, Nro 16. Sivut 2075-2089.
@article{3823c03c6f8c45ef89cda167fa5284f7,
title = "Lysophosphatidic acid and sphingosine-1-phosphate promote morphogenesis and block invasion of prostate cancer cells in three-dimensional organotypic models",
abstract = "Normal prostate and some malignant prostate cancer (PrCa) cell lines undergo acinar differentiation and form spheroids in three-dimensional (3-D) organotypic culture. Acini formed by PC-3 and PC-3M, less pronounced also in other PrCa cell lines, spontaneously undergo an invasive switch, leading to the disintegration of epithelial structures and the basal lamina, and formation of invadopodia. This demonstrates the highly dynamic nature of epithelial plasticity, balancing epithelial-to-mesenchymal transition against metastable acinar differentiation. This study assessed the role of lipid metabolites on epithelial maturation. PC-3 cells completely failed to form acinar structures in delipidated serum. Adding back lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) rescued acinar morphogenesis and repressed invasion effectively. Blocking LPA receptor 1 (LPAR1) functions by siRNA (small interference RNA) or the specific LPAR1 inhibitor Ki16425 promoted invasion, while silencing of other G-protein-coupled receptors responsive to LPA or S1P mainly caused growth arrest or had no effects. The G-proteins Gα12/13 and Gαi were identified as key mediators of LPA signalling via stimulation of RhoA and Rho kinases ROCK1 and 2, activating Rac1, while inhibition of adenylate cyclase and accumulation of cAMP may be secondary. Interfering with these pathways specifically impeded epithelial polarization in transformed cells. In contrast, blocking the same pathways in non-transformed, normal cells promoted differentiation. We conclude that LPA and LPAR1 effectively promote epithelial maturation and block invasion of PrCa cells in 3-D culture. The analysis of clinical transcriptome data confirmed reduced expression of LPAR1 in a subset of PrCa's. Our study demonstrates a metastasis-suppressor function for LPAR1 and Gα12/13 signalling, regulating cell motility and invasion versus epithelial maturation.",
keywords = "1182 Biochemistry, cell and molecular biology, Prostate cancer, LYSOPHOSPHATIDIC ACID, sphingosine-1-phosphate, 3122 Cancers, prostate cancer, Invasion",
author = "Ville H{\"a}rm{\"a} and Matias Knuuttila and Johannes Virtanen and Tuomas Mirtti and Pekka Kohonen and Kovanen, {Panu Esko} and A Happonen and S Kaewphan and I Ahonen and Olli Kallioniemi and Matthias Nees and R Grafstr{\"o}m and J L{\"o}tj{\"o}nen",
year = "2012",
doi = "10.1038/onc.2011.396",
language = "English",
volume = "31",
pages = "2075--2089",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "16",

}

Härmä, V, Knuuttila, M, Virtanen, J, Mirtti, T, Kohonen, P, Kovanen, PE, Happonen, A, Kaewphan, S, Ahonen, I, Kallioniemi, O, Nees, M, Grafström, R & Lötjönen, J 2012, 'Lysophosphatidic acid and sphingosine-1-phosphate promote morphogenesis and block invasion of prostate cancer cells in three-dimensional organotypic models' Oncogene, Vuosikerta 31, Nro 16, Sivut 2075-2089. https://doi.org/10.1038/onc.2011.396

Lysophosphatidic acid and sphingosine-1-phosphate promote morphogenesis and block invasion of prostate cancer cells in three-dimensional organotypic models. / Härmä, Ville; Knuuttila, Matias; Virtanen, Johannes; Mirtti, Tuomas; Kohonen, Pekka; Kovanen, Panu Esko; Happonen, A; Kaewphan, S; Ahonen, I; Kallioniemi, Olli; Nees, Matthias; Grafström, R; Lötjönen, J.

julkaisussa: Oncogene, Vuosikerta 31, Nro 16, 2012, s. 2075-2089.

Tutkimustuotos: ArtikkelijulkaisuArtikkeliTieteellinenvertaisarvioitu

TY - JOUR

T1 - Lysophosphatidic acid and sphingosine-1-phosphate promote morphogenesis and block invasion of prostate cancer cells in three-dimensional organotypic models

AU - Härmä, Ville

AU - Knuuttila, Matias

AU - Virtanen, Johannes

AU - Mirtti, Tuomas

AU - Kohonen, Pekka

AU - Kovanen, Panu Esko

AU - Happonen, A

AU - Kaewphan, S

AU - Ahonen, I

AU - Kallioniemi, Olli

AU - Nees, Matthias

AU - Grafström, R

AU - Lötjönen, J

PY - 2012

Y1 - 2012

N2 - Normal prostate and some malignant prostate cancer (PrCa) cell lines undergo acinar differentiation and form spheroids in three-dimensional (3-D) organotypic culture. Acini formed by PC-3 and PC-3M, less pronounced also in other PrCa cell lines, spontaneously undergo an invasive switch, leading to the disintegration of epithelial structures and the basal lamina, and formation of invadopodia. This demonstrates the highly dynamic nature of epithelial plasticity, balancing epithelial-to-mesenchymal transition against metastable acinar differentiation. This study assessed the role of lipid metabolites on epithelial maturation. PC-3 cells completely failed to form acinar structures in delipidated serum. Adding back lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) rescued acinar morphogenesis and repressed invasion effectively. Blocking LPA receptor 1 (LPAR1) functions by siRNA (small interference RNA) or the specific LPAR1 inhibitor Ki16425 promoted invasion, while silencing of other G-protein-coupled receptors responsive to LPA or S1P mainly caused growth arrest or had no effects. The G-proteins Gα12/13 and Gαi were identified as key mediators of LPA signalling via stimulation of RhoA and Rho kinases ROCK1 and 2, activating Rac1, while inhibition of adenylate cyclase and accumulation of cAMP may be secondary. Interfering with these pathways specifically impeded epithelial polarization in transformed cells. In contrast, blocking the same pathways in non-transformed, normal cells promoted differentiation. We conclude that LPA and LPAR1 effectively promote epithelial maturation and block invasion of PrCa cells in 3-D culture. The analysis of clinical transcriptome data confirmed reduced expression of LPAR1 in a subset of PrCa's. Our study demonstrates a metastasis-suppressor function for LPAR1 and Gα12/13 signalling, regulating cell motility and invasion versus epithelial maturation.

AB - Normal prostate and some malignant prostate cancer (PrCa) cell lines undergo acinar differentiation and form spheroids in three-dimensional (3-D) organotypic culture. Acini formed by PC-3 and PC-3M, less pronounced also in other PrCa cell lines, spontaneously undergo an invasive switch, leading to the disintegration of epithelial structures and the basal lamina, and formation of invadopodia. This demonstrates the highly dynamic nature of epithelial plasticity, balancing epithelial-to-mesenchymal transition against metastable acinar differentiation. This study assessed the role of lipid metabolites on epithelial maturation. PC-3 cells completely failed to form acinar structures in delipidated serum. Adding back lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) rescued acinar morphogenesis and repressed invasion effectively. Blocking LPA receptor 1 (LPAR1) functions by siRNA (small interference RNA) or the specific LPAR1 inhibitor Ki16425 promoted invasion, while silencing of other G-protein-coupled receptors responsive to LPA or S1P mainly caused growth arrest or had no effects. The G-proteins Gα12/13 and Gαi were identified as key mediators of LPA signalling via stimulation of RhoA and Rho kinases ROCK1 and 2, activating Rac1, while inhibition of adenylate cyclase and accumulation of cAMP may be secondary. Interfering with these pathways specifically impeded epithelial polarization in transformed cells. In contrast, blocking the same pathways in non-transformed, normal cells promoted differentiation. We conclude that LPA and LPAR1 effectively promote epithelial maturation and block invasion of PrCa cells in 3-D culture. The analysis of clinical transcriptome data confirmed reduced expression of LPAR1 in a subset of PrCa's. Our study demonstrates a metastasis-suppressor function for LPAR1 and Gα12/13 signalling, regulating cell motility and invasion versus epithelial maturation.

KW - 1182 Biochemistry, cell and molecular biology

KW - Prostate cancer

KW - LYSOPHOSPHATIDIC ACID

KW - sphingosine-1-phosphate

KW - 3122 Cancers

KW - prostate cancer

KW - Invasion

U2 - 10.1038/onc.2011.396

DO - 10.1038/onc.2011.396

M3 - Article

VL - 31

SP - 2075

EP - 2089

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 16

ER -